It is widely known that PPARγ activators are useful as therapeutic drugs for type 2 diabetes mellitus, as seen in examples such as rosiglitazone and pioglitazone. PPARγ is considered to have various physiological functions such as inducement of differentiation into adipocytes and adjustment of biogenic energy metabolism (for example, refer to Non-patent Documents 1 and 2). On the other hand, it has been reported that PPARγ activators induce differentiation, cell cycle inhibition or apotosis against certain types of cancer cells, and cause growth inhibition of cancer cells (for example, refer to Non-patent Documents 3, 4 and 5). In addition to these findings, since chromosomal translocation of PAX8-PPARγ has been frequently observed and the function of PPARγ is inactivated in thyroid cancer, and since a point mutation which causes dysfunction, though not high in frequency, is observed in colon cancer, it has been suggested that PPARγ acts in an inhibitory manner against oncogenic transformation (for example, refer to Patent Documents 6 and 7). From these findings, the possibility of PPARγ activator potency for treating cancer has been considered, and small clinical tests have been conducted with cancer patients by using rosiglitazone. However, sufficient efficiency was not observed (for example, refer to Patent Document 8). Thus far, the reason for this result has not been discovered; however, it is highly likely that the anti-cancer effect by rosiglitazone was not strong enough. Accordingly, finding a PPARγ activator which has a stronger anti-cancer effect is expected to contribute greatly to the treatment of cancer in future.
On the other hand, in recent cancer treatments, an approach in which a plurality of anti-cancer drugs are used in combination to increase the efficiency of the drugs and to reduce side effects, compared with the case where each of the drugs is administered separately, has been attempted. As types of anti-cancer drugs used in combination treatment, cytocidal cancer chemotherapy drugs and various molecular target drugs that have been newly introduced to the market recently, can be mentioned. In particular, molecular target drugs are generally low in side effects compared with the former, and it is often the case that there is no need to decrease the usage amount of the former to prevent side effects from increasing, with respect to combination administration. Therefore, in combination therapy, since the efficiency of cytocidal cancer chemotherapy drugs can be obtained to the maximum and since their effect can be enhanced by the drug efficacy of molecular target drugs, development of various drugs that target molecules is conducted extensively at present. Examples of molecular target drugs which are presently gaining attention are bevacizumab (product name Avastin) which is an antibody medicament having anti-angiogenesis activity, and gefitinib (product name Iressa) and erlotinib (product name Tarceva), which are epidermal growth factor receptor (EGFR) inhibitors. In addition, sorafenib, which has anti-angiogenesis (vascular endothelial growth factor receptor (VEGFR) inhibitory) activity in combination with Raf kinase inhibitory activity and is presently in the stage of clinical testing, is also suggested to have efficiency in clinical tests and is gaining attention. As described, the indication that anti-cancer effects can be enhanced by combination administration with these molecular target drugs enables various treatment options to be provided to a patient when considering a cancer treatment, and thus greatly contributes to improvement in treatment outcome. Here, the enhancement of anti-cancer efficiency by combination administration generally indicates that the efficiency obtained by combination administration is superior to the efficiency obtained by single administration of each drug (for example, refer to Non-patent Document 9), and the clinical significance is considered to be large even when a synergistic enhancing effect cannot be obtained.
Japanese Patent No. 3488099 (for others, refer to Patent Documents 1 and 2) discloses a thiazolidinedione compound having a novel chemical structure. A compound represented by the general formula (I), which is contained as an active ingredient of the anti-cancer pharmaceutical composition according to the present invention, is a compound which is embraced in the scope of compounds relating to the thiazolidinedione compound disclosed in the patent. Japanese Patent No. 3488099 discloses that the thiazolidinedione compound disclosed in the published patent has PPARγ activation potency and can be used as an anti-cancer drug. However, the patent does not disclose any specific test data which shows that the thiazolidinedione compound actually has an anti-cancer action.
Further, pharmaceutical compositions which contain this thiazolidinedione compound and another drug have been reported.
For example, a pharmaceutical composition containing this thiazolidinedione compound and a MAP kinase inhibitor has been reported (refer to Patent Documents 3 and 4), and it is disclosed that this pharmaceutical composition is useful as a preventive drug, a therapeutic drug or as a cell proliferation inhibitor of cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer or liposarcoma.
In addition, a pharmaceutical composition for prophylaxis or treatment of cancer which contains some of the compounds included in the scope of compounds relating to the aforementioned thiazolidinedione compound and a RXR (retinoid X receptor) activator has been reported (refer to Patent Documents 5 and 6), and it is disclosed that this pharmaceutical composition is useful as a therapeutic drug or as a preventive drug for especially lung cancer, gastric cancer or colon cancer.
A pharmaceutical composition containing the aforementioned thiazolidinedione compound and a fluorouracil type antimetabolite or a platinum complex has been reported (refer to Patent Documents 7 and 8), and it is disclosed that this pharmaceutical composition is useful especially as a preventive drug, a therapeutic drug or as a cell proliferation inhibitor of cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer or liposarcoma.
A pharmaceutical composition containing the aforementioned thiazolidinedione compound and a diuretic drug has been reported (refer to Patent Documents 9 and 10), and it is disclosed that this pharmaceutical composition can prevent or treat side effects that are caused when PPARγ activator is administered, such as hypercardia, edema, fluid retention, and pleural effusion retention, and is useful especially as a preventive drug, a therapeutic drug or as a cell proliferation inhibitor of cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer or liposarcoma.
A pharmaceutical composition containing the aforementioned thiazolidinedione compound and a novel sulfamide compound having MEK inhibitory activity has been reported (refer to Patent Documents 11 and 12), and it is disclosed that this pharmaceutical composition is useful especially as a preventive drug, a therapeutic drug or as a cell proliferation inhibitor of cancer such as gastric cancer, lung cancer, breast cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, leukemia, head and neck cancer or liposarcoma.    [Patent Document 1] U.S. Pat. No. 6,432,993    [Patent Document 2] EP Patent No. 1022272    [Patent Document 3] Japanese Patent Application (Kokai) No. 2003-192592    [Patent Document 4] Pamphlet of International Publication No. WO 03/032988    [Patent Document 5] Japanese Patent Application (Kokai) No. 2003-238406    [Patent Document 6] Pamphlet of International Publication No. WO 03/053440    [Patent Document 7] Japanese Patent Application (Kokai) No. 2004-83558    [Patent Document 8] Pamphlet of International Publication No. WO 03/082865    [Patent Document 9] Japanese Patent Application (Kokai) No. 2004-83574    [Patent Document 10] Pamphlet of International Publication No. WO 2004/000356    [Patent Document 11] Japanese Patent Application (Kokai) No. 2005-162727    [Patent Document 12] Pamphlet of International Publication No. WO 2004/083167    [Non-patent Document 1] Spiegelman B M. PPAR-γ: Adipogenic regulator and thiazolidinedione receptor. Diabetes, 1998; 47: 507-14.    [Non-patent Document 2] Lehmann J M, Moore L B et al. An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor gamma. J Biol Chem 1995; 270: 12953-6.    [Non-patent Document 3] Mueller E, Sarraf P et al. Terminal differentiation of the human breast cancer through PPAR gamma. Mol Cell 1998; 1: 465-70.    [Non-patent Document 4] Yoshizume T, Ohta T et al. Thiazolidinedione, a peroxisome proliferator-activated receptor gamma ligand, inhibits growth and metastasis of HT-29 human colon cancer cells through differentiation-promoting effects. Int J Oncol 2004; 25: 631-9.    [Non-patent Document 5] Ray D M, Bernstein S H et al. Human multiple myeloma cells express peroxisome proliferator-activated receptor γ and undergo apoptosis upon exposure to PPARγ ligands. Clin Immunology, 2004; 113: 203-13.    [Non-patent Document 6] Dwight T, Thoppe S R, et al. Involvement of the PAX8/peroxisome proliferator-activated receptor gamma rearrangement in follicular thyroid tumors. J Clin Endocrinol Metab 2003; 88: 4440-5.    [Non-patent Document 7] Sarraf P, Mueller E et al. Loss-of-function mutations in PPAR gamma associated with human colon cancer. Mol Cell 1999; 3: 799-804.    [Non-patent Document 8] Debrock G, Vanhentenrijk V et al. A phase II trial with rosiglitazone in liposarcoma patients. Br J Cancer 2003; 89: 1409-12.    [Non-patent Document 9] Tatsuo Saito ed., Development of Drug Therapy for Cancer and Evaluation of Efficiency, Realize inc., pp. 128-138 (1985).